Cells of the monocyte/macrophage (M/M) lineage represent important targets of HIV infection. Cells of the M/M syste are differentially susceptible to HIV infection, depending on virus strains, the sate of cellular differetiation, and localization of these cells in vivo. Certain types of HIV strains replicate will in macrophages (M-tropic), while other replicate only in CD4+T cells (T-tropic). M-tropic strains utilize CCR5, a receptor for the CC chemokines RANTES, MI-1 alpha and MIP-1 beta, as a major co-receptor for viural entry, while CXCR4, a receptor for the CXC chemokine SDF-1, serves as a major entry co-receptor for T-tropic viral strains. Resistance of macrophages to infection with T-tropic HIV-1 strains remains a paradox, since these cells express both CD4 and CXCR4. With regard to the relationship between cellular differentiation and susceptibility to HIV infection, promonocytes and monocytes are much less susceptible to HIV infection than mature macrophages and promonocytes are usually susceptibel to T-tropic HIV-1 but not M-tropic HIV-1. Finally, macrophages in certain tissues such as brain, skin and the gastrointestinal tract harbor HIV more frequently than those in other tissues such as liver. In oreder to address these issues, we have established an in vitro experimental system using promonocytic U937 cell clones. We have demonstrated that certain U937 clones are highly susceptible to T-tropic HIV types (these are termed "plus" clones), while others are resisant (termed "minus" clones). Plus clones become susceptible to M-tropic HIV upon differentiation with retinoic acid, while minus clonoes remain refractory to either strain of HIV; minus clones are resistant to HIV at viral fusion/entry step, despite the fact that they express CD4 (an HIV receptor) as well as appropriate co-receptors.